The compounds spiro[2.5]octane-5,7-dione and spiro[3.5]nonane-6,8-dione are useful and important intermediates for the preparation of pharmaceutically active substances. Several routes to them are known and are quite challenging. However, they all suffer from severe drawbacks from a chemical process point of view. Therefore, it is a demand for developing efficient and robust methods to synthesize spiro[2.5]octane-5,7-dione and spiro[3.5]nonane-6,8-dione in order to circumvent these problems.
Up to now, several routes to synthesize spiro[2.5]octane-5,7-dione and spiro[3.5]nonane-6,8-dione have been described in published papers or patents applications.
WO 2012052451 and WO 2012085166 describe a four-step (two operations) synthesis of spiro[2.5]octane-5,7-dione (3) via Wittig reaction, Michael/Claisen reactions followed by hydrolysis and decarboxylation using (1-ethoxycyclopropoxy)trimethylsilane (1) as the starting material (Scheme 1). The disadvantage of this approach is that flash chromatography is used for the purification of intermediate and final product, which is not practical for scale-up. Additionally, the use of o-dichlorobenzene and sodium hydride which is used quite often on laboratory scale is not ideal in the pilot or manufacture scale either.

Angew. Chem. Intl. Ed., 38(22), 3373-3375, 1999 describes the synthesis of spiro[3.5]nonane-6,8-dione (6) via a similar protocol as above. The starting material is cyclobutanone (4). Due to the less activity of the Wittig reagent (MeC(O)CH═PPh3) and the low volatile property of cyclobutanone (4), the first step can only be carried out at 100° C. to increase the reactivity and in silicon oil to avoid the loss of cyclobutanone (4) from the reaction system. After the reaction, the enone (5) has to be distilled out from the silicon oil in order to proceed to the next step (Scheme 2).

Org. Proc. Res. Dev. 7(6), 913-916, 2003 describes synthesis of spiro[3.5]nonane-6,8-dione (6) via hexenone (7) (Scheme 3).

Therefore, there is a strong need for developing a novel and practical process to synthesize spiro[2.5]octane-5,7-dione (3) and/or spiro[3.5]nonane-6,8-dione (6), which could allow to use the above mentioned starting materials ((1-ethoxycyclopropoxy)trimethylsilane (1) and/or cyclobutanone (4)) and provide the desired products in high quality and good chemical yield without involvement of chromatography purification and usage of uncommon organic solvents and reagents.